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Updated: Apr 6, 2026
A Mouse Model of Chronic Liver Fibrosis for the Study of Biliary Atresia
Published on: February 3, 2023
Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia
Tatiana Iordanskaia1, Miroslav Malesevic2, Gunter Fischer3
1Division of Pediatric Surgery, Children's National Medical Center, Washington, District of Columbia, United States of America.
Insights
Extracellular cyclophilin A (CypA) drives biliary atresia (BA) inflammation via the SMAD pathway. A novel drug, MM284, targeting extracellular CypA, shows promise in treating experimental BA by reducing inflammation and fibrosis.
Area of Science:
- Hepatology
- Immunology
- Molecular Biology
Background:
- Biliary atresia (BA) is a severe pediatric liver disease of unknown cause, leading to bile duct obstruction, inflammation, and liver failure.
- The SMAD signaling pathway is implicated in BA pathogenesis, but the initiating factors remain unclear.
- Extracellular cyclophilin A (CypA) is a known pro-inflammatory factor.
Purpose of the Study:
- To investigate the role of extracellular cyclophilin A (CypA) in biliary atresia (BA) pathogenesis.
- To evaluate the therapeutic potential of a novel extracellular cyclophilin inhibitor, MM284, in a murine model of BA.
Main Methods:
- Utilized the rhesus rotavirus (RRV) murine model to induce experimental biliary atresia (BA).
- Administered MM284, a cell-impermeable cyclosporine A derivative, to mice before or after RRV infection.
- Assessed physiological parameters (weight gain, bilirubinuria), liver histology (inflammation), and molecular markers (SMAD pathway, MMPs, TIMP-4).
- Treated human hepatic stellate cells with recombinant cyclophilin and MM284 to confirm pathway activation and inhibition.
Main Results:
- RRV infection significantly increased plasma levels of extracellular cyclophilin A (CypA).
- MM284 treatment improved BA outcomes, including restored weight gain, abolished bilirubinuria, and reduced liver inflammation.
- MM284 treatment suppressed SMAD pathway activation and downstream fibrosis mediators (TIMP-4, MMP-7) in experimental BA.
- Recombinant cyclophilin induced SMAD2/3 activation in human hepatic stellate cells, which was inhibited by MM284.
Conclusions:
- Extracellular cyclophilins activate the SMAD pathway, contributing to inflammation and fibrosis in experimental biliary atresia (BA).
- MM284 effectively inhibits extracellular CypA, ameliorates BA pathology in a murine model, and warrants further investigation as a therapeutic agent.
- This study suggests a novel therapeutic strategy targeting extracellular cyclophilins for BA and potentially other chronic liver diseases.
Abstract:
Biliary atresia (BA) is a devastating liver disease of unknown etiology affecting children generally within the first 3 months of life. The disease is manifested by inflammation and subsequent obstruction of the extrahepatic bile ducts, fibrosis and liver failure. The mechanisms responsible for disease pathogenesis are not fully understood, but a number of factors controlled by the SMAD signaling pathway have been implicated. In this study, we investigated the role of a known proinflammatory factor, extracellular cyclophilin A (CypA), in the pathogenesis of biliary atresia using the rhesus rotavirus (RRV) murine model. We used a unique cyclosporine A derivative, MM284, which does not enter cells and therefore inactivates exclusively extracellular cyclophilins, as a potential treatment. We demonstrated that levels of CypA in plasma of RRV-infected mice were increased significantly, and that treatment of mice with MM284 prior to or one day after disease initiation by RRV infection significantly improved the status of mice with experimental BA: weight gain was restored, bilirubinuria was abrogated, liver infiltration by inflammatory cells was reduced and activation of the SMAD pathway and SMAD-controlled fibrosis mediators and tissue inhibitor of metalloproteinases (TIMP)-4 and matrix metalloproteinase (MMP)-7 was alleviated. Furthermore, treatment of human hepatic stellate cells with recombinant cyclophilin recapitulated SMAD2/3 activation, which was also suppressed by MM284 treatment. Our data provide the first evidence that extracellular cyclophilins activate the SMAD pathway and promote inflammation in experimental BA, and suggest that MM284 may be a promising therapeutic agent for treating BA and possibly other intrahepatic chronic disorders.
